Tuberculosis alters immune-metabolic pathways resulting in perturbed IL-1 responses Alba Llibre1, Nikaïa Smith1, Vincent Rouilly2, Munyaradzi Musvosvi3, Elisa Nemes3, Céline Posseme1, Simba Mabwe3, Bruno Charbit4, Stanley Kimbung Mbandi3, Elizabeth Filander3, Hadn Africa3 Violaine Saint-André1,5, Vincent Bondet1, Pierre Bost6,7, Humphrey Mulenga3, Nicole Bilek3, Matthew L Albert8, Thomas J Scriba3, Darragh Duffy1,4. 1 Translational Immunology Lab, Institut Pasteur, Paris, France 2 DATACTIX, Paris, France; 3 South African Tuberculosis Vaccine Initiative (SATVI), Division of Immunology, Department of Pathology and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa; 4 Center for Translational Research, Institut Pasteur, Paris, France; 5 Bioinformatics and Biostatistics HUB, Computational Biology Department, Institut Pasteur, USR 3756 CNRS, Paris, France 6 Sorbonne Université, Complexité du vivant, F-75005 Paris, France; 7 Systems Biology Group, Center for Bioinformatics, Biostatistics, and Integrative Biology (C3BI) and USR 3756, Institut Pasteur CNRS, 8 Insitro, San Francisco, California, USA. ABSTRACT Tuberculosis (TB) remains a major public health problem and new therapies are urgently needed to end the epidemic, as specified in the WHO Global Tuberculosis Report 2020. Host-directed therapeutics offer great potential as novel treatment strategies. However, their successful development still requires a comprehensive understanding of how Mycobacterium tuberculosis (M.tb) infection impacts immune and metabolic responses. To address this challenge, we applied standardised immunomonitoring tools to compare induced immune responses between individuals with latent M.tb infection (LTBI) and active TB disease, at diagnosis and after cure. This revealed distinct responses between TB and LTBI groups at transcriptomic, proteomic and metabolomic levels. At baseline, we identified pregnane steroids and the PPARγ pathway as new immune-metabolic drivers of elevated plasma IL-1ra in TB. We also observed dysregulated induced IL-1 responses after BCG stimulation in TB patients. These were explained by differences in TNF, type I IFN signalling and granzyme mediated cleavage. Finally the downstream signalling response to IL-1β was also dramatically perturbed in TB disease but was completely restored after successful antibiotic treatment. This systems immunology approach improves our knowledge of how M.tb alters immune responses, and may support design of improved prophylactic and therapeutic tools that will aid TB eradication.